Obesity affects 33% of American adults and produces or exacerbates many complications including diabetes, hypertension, cardiovascular disease, strokes, and cancer. Current medical treatments are poorly effective and surgical treatments are associated with significant side effects. The overall goals of this proposal are to determine the mechanisms of action of a new surgical procedure for obesity, and specifically to evaluate changes in energy metabolism and factors affecting the sympathetic nervous system (SNS). Preliminary data show that a combination of vagotomy and ileal transposition surgery (VIT) in rats produces long term weight loss without long term reduction in energy intake, and that energy expenditure in VIT rats is increased vs control animals who were food restricted to match the weights of the VIT rats. Initial whole animal studies suggest that the VIT effect is due in part to enhanced sensitivity and responsiveness to adrenergic stimuli, and that these effects also are present at the cellular level. In vivo and in vitro studies will compare VIT rats to two sham surgical control groups: 1) ad lib fed sham vagotomy-sham IT rats (SV-SIT) and 2) SV-SIT rats pair weight matched to VIT rats by food restriction (R-SV-SIT). The specific aims for the in vivo studies are to use indirect calorimetry to assess energy expenditure (EE) in VIT and control rats with perturbations that stimulate the SNS, including fasting vs fed state, could exposure, and norepinephrine (NE) infusion. Also to assess uncoupling protein (UCP) and UCP mRNA in brown adipose tissue, NE turnover in multiple organs, and the ability to adrenergic antagonists to prevent weight loss with VIT. The specific aims of the in vitro studies are to measure sensitivity and responsiveness to norepinephrine in the following models: 1) isolated adipocytes from VIT and control rats, 2) isolated adipocytes from normal rats that have been incubated with plasma from VIT and control rats, and 3) 3T3-L1 cells in tissue culture that have been incubated with plasma from VIT and control rats. Understanding the mechanisms of weight loss with obesity surgery may allow development of better medical and/or surgical procedures to treat obesity.